PROJECT SUMMARY/ABSTRACT. The underlying mechanisms of uveitis, or intraocular inflammation, remain poorly understood. However, a recently identified gene called NOD2 provides important insight into the genetics involved in the pathogenesis of uveitis. Specific mutations within NOD2 are the cause of an inherited multisystem granulomatous disease affecting the eye, joints and skin that develop in the absence of infection. While pathogenic mutations have been identified, the functions of NOD2 responsible for initiation of ocular inflammation have not. We have succeeded in establishing a model of NOD2-dependent uveitis, wherein NOD2 is activated by its synthetic agonist muramyl dipeptide (MDP). We propose to use this model to investigate the mechanisms by which NOD2 could initiate uveitis either via its direct activation by its agonist (in the absence of infection as might occur in Blau syndrome) or by its ability to regulate inflammation induced by either toll-like receptors (TLRs) or by the homologous family member, NOD1. Specifically, we will 1) Identify which cells respond to MDP and investigate the role of IFNg as a modulator of NOD2-driven ocular inflammation; 2) Since our discovery that NOD1 triggers uveitis, we propose to investigate whether NOD1 and NOD2-induced ocular inflammatory response are distinguishable and whether cross-talk occurs; and 3) Since NOD2 appears to exert its most measurable biological effects when it modulates TLRs, we will explore the capacity of NOD2 to regulate TLR responses within the eye. This aim will also explore how MDP affects the inflammatory response triggered by IL-1b. Together, these studies will have considerable implications for understanding pathological mechanisms involved in uveitis. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE/SIGNIFICANCE. Experiments in nature can lead to personal suffering while concomitantly offering unique opportunities to elucidate human biology. This is best exemplified in Blau syndrome, wherein a single base pair change in the NOD2 gene results in complete penetrance for the induction of uveitis and multisystem granulomatous disease. The connection between a single gene and uveitis offers enormous potential to study the pathogenesis of uveitis.